Common clonal origin of central and resident memory T cells following skin immunization

Central memory T (T-CM) cells in lymph nodes (LNs) and resident memory T (T-RM) cells in peripheral tissues have distinct roles in protective immunity(1-5). Both are generated after primary infections, but their clonal origins have been unclear. To address this question, we immunized mice through the skin with a protein antigen, a chemical hapten, or a non-replicating poxvirus. We then analyzed antigen-activated T cells from different tissues using high-throughput sequencing (HIS) of the gene encoding the T cell receptor (TCR) beta-chain (Trb, also known as Tcrb) using CDR3 sequences to simultaneously track thousands of unique T cells(6). For every abundant T-RM cell clone generated in the skin, an abundant T-CM cell clone bearing the identical TCR was present in the LNs. Thus, antigen-reactive skin T-RM and LN T-CM cell clones were derived from a common naive T cell precursor after skin immunization, generating overlapping TCR repertoires. Although they bore the same TCR, T-RM cells mediated rapid contact hypersensitivity(7) responses, whereas T-CM cells mediated delayed and attenuated responses. Studies in human subjects confirmed the generation of skin T-RM cells in allergic contact dermatitis. Thus, immunization through skin simultaneously generates skin T-RM and LN T-CM cells in similar numbers from the same naive T cells.